Basis for G Protein Activation

When a flexible five-glycine linker is inserted between the C-terminus and the 75 helix, receptor binding is only slightly decreased while receptor-catalyzed nucleotide exchange is severely impaired. Alternatively, doubling the length of the a5 helix by repeating its sequence has only a 

Bound GDP is buried between the GTPase and helical domains of Ga. Some of the contacts between these two domains may need to be broken 

Outside of the Ga subunit, two models for receptor-mediated GDP release involve an active role for the G/]y subunit (Fig. 7). These models are based on the hypothesis that Gfiy functions in heterotrimeric G proteins as a structural homologue to the guanine nucleotide exchange factors for 

Despite the fundamental importance of receptor-catalyzed G protein activation in cellular signaling, relatively little is known about this process as compared to the other regulatory events in the G protein cycle. Crystal structures of inactive rhodopsin and G protein heterotrimers provide the structural context for the meaningful interpretation of the results of the numerous biochemical and biophysical studies described in the preceding sections. Enough data has been accumulated to begin to develop rudimentary models of the receptor-G protein complex that meet some of 

Particularly important information will come from additional distance constraints between the receptor and G protein, such as novel cross-links or interprobe measurements from fluorescence or electron paramagnetic resonance spectroscopy. Initially, relatively few long-range distance constraints would be necessary to define the relative orientation of the receptor and G protein, which is a fundamental but unanswered question about the complex. Once the proper orientation has been established experimentally, the model will suggest additional distance measurements that will be necessary to pin down the receptor s intracellular loops onto the surface of the G protein. Proceeding in such an iterative fashion should provide the experimental evidence that is critically important in refining the current models of the receptor—G protein complex. 

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